Plasmapheresis (the removal of blood, separation of the plasma and the reinfusion of the blood cells) with or without the replacement of the patient's plasma by donor plasma, a plasma fraction, or other physiological solution, is becoming more useful in the clinical treatment of various disease states. Such disease states have in common the presence of undesirable elevated levels of plasma solutes. Such solutes (due to their increased size) cannot be effectively removed by techniques such as dialyses and hemofiltration. Therefore plasma removal with the infusion of physiological solutions is effective in depleting their concentration. Various disease states treated by plasmapheresis are as follows.
Myasthenia gravis PA0 Glomerulonephritis PA0 Goodpasture's syndrome PA0 Skin diseases PA0 Severe asthma PA0 Immune complex diseases PA0 Diabetic hypertriglyceridemia PA0 Hypercholesterolemia PA0 Macroglobulinemia PA0 Hematological diseases PA0 Raynaud's disease and phenomenon PA0 Renal transplantation PA0 Rhesus incompatibility PA0 Hepatic coma PA0 Hypertension PA0 Motor neurone disease PA0 Refsum's disease PA0 Guillain-Barre syndrome PA0 Arthritis PA0 Removal of protein bound toxins PA0 Cancer PA0 Insulin resistant diabetes
pemphigus PA1 herpes gestationis PA1 crescentic nephritis PA1 systemic lupus erythematosus PA1 Wegner's/polyarteritis PA1 subacute bacterial endocarditis PA1 cryoglobulinemia PA1 cutaneous vasculitis PA1 Waldenstrom's syndrome PA1 hyperviscosity syndromes PA1 paraproteiniemias, myeloma PA1 hemolytic anemia PA1 red cell agglutinins PA1 auto-antibody lymphocytes PA1 thrombotic thromcocytopenia PA1 purpura PA1 immune thrombocytopenia PA1 factor VIII inhibitor PA1 or antibodies PA1 amyotrophic lateral sclerosis PA1 auto polyneuropathy PA1 poisons--methyl parathion, PA1 poisonous mushrooms, paraquat PA1 hormones--thyroid PA1 protein bound aluminum--dialysis PA1 dementia
While this list is not exhaustive, it exemplifies the wide range of diseases associated with biochemical abnormalities; such biochemical agents being of high molecular weight.
At present the number of cases of plasma exchange are small and in many instances without controls. The success in some cases is quite impressive.
The treatments presently being carried out by plasmapheresis may be generally grouped into two types: (1) removal of an abnormal metabolite(s) or toxin(s) and (2) treatment of a disorder of the immune system. Examples of the first type include hepatic support, hypertriglyceridemia, hypercholesterolemia, and the removal of protein or lipid bound toxins. Examples of the second type include myasthenia gravis, glomerulonephritis, macroglobulinemias, arthritis, and systemic lupus erythematosis.
While in some of the diseases there is little known concerning the correlation of the disease with the increased plasma factors, for other diseases the factor(s) is known or correlation between the increased factor and the disease state can be shown as outlined in Table 1 and Table 2 as follows.
TABLE 1 ______________________________________ IMMUNOLOGICAL DISORDERS TREATED BY PLASMAPHERESIS Increased Factor(s) or Disease Abnormality ______________________________________ Myasthenia gravis Antibody specific for acetyl- choline receptor Renal transplant rejection Antibody to glomerular base- ment membrane Goodpasture's syndrome Antibody to basement membrane of lung Rhesus incompatibility Anti-D-antibody Systemic lupus erythema- DNA antibodies and immune tosus complexes of DNA Glomerulonephritis Immune complexes or auto- antibodies Macroglobulinemia IgM and hyperviscosity (Waldenstrom's syndrome) Pemphigus vulgaris IgG antibodies Asthma bronchitis IgE Myeloma Myeloma globulin Raynaud's disease and Macroglobulin, increased vis- pnenomena cosity Thrombocytopenic purpura Immunocomplex Cancer .alpha.-1, .alpha.-2 globulines, .beta.-globulins, .alpha.-1-antitryp- sin, ceruloplasmin, orosomu- coid, haptoglobin, IgA Breast cancer Circulating immune complex Polyneuropathy Antibodies to myelin Rheumatoid arthritis "Serum factor" Diabetes Autoantibodies to insulin receptor Autoimmune hemolytic Antibody to RBC anemia ______________________________________
TABLE 2 ______________________________________ METABOLIC DISORDERS TREATED BY PLASMAPHERESIS Increased Factor(s) or Disease Abnormality ______________________________________ Hepatic coma Metabolic factors (bilirubin) Refsum's disease Phytanic acid (bound to lipo- proteins) Poisonings Protein bound drug Dialysis dementia Protein bound aluminum Hypertriglyceridemia Triglycerides and hypervis- cosity Hypercholesterolemia Cholesterol Amytrophic lateral Cytotoxic factors, immune sclerosis complexes suspected ______________________________________
Listed are various diseases for which increased levels of antibodies or macromolecules exist and for which plasmapheresis has been useful by its reduction of these substances. For example, in myasthenia gravis, antibodies specific for the acetycholine receptors are elevated. Removal of these antibodies by plasmapheresis shows improvement in the patients. In macroglobulinemia, there is an increased level of gamma globulin. Reducing this level by plasmapheresis is clinically effective.
The conventional method of plasmapheresis employs a cell centrifuge involving bulky and expensive equipment which is not portable and is very costly, and carries with its potential hazards. Namely, essential plasma products are lost that are not being replenished in the substitution fluids and the potential exists for acquiring hepatitis. In addition, the effectiveness of the procedure is limited due to the limited removal that can be accomplished in discarding a limited volume. If conventional plasmapheresis were to be accepted for the treatment of many of these diseases there would be created a greater need for plasma products than could be met nationally. Obviously, to take advantage of plasmapheresis in treating these diseases, new techniques must be developed for removal of the plasma "toxins".
A major improvement would be to develop "on-line" removal systems to remove the "toxin" in question and to return the treated plasma back to the patient. The advantages are quite obvious. The recent development of membrane systems for the on-line removal of plasma from whole blood has added impetus to the development work. Extracorporeal treatment of plasma generated by either membrane plasma separators or centrifuges has been carried out by either specific or non-specific sorbents such as activated charcoal, nonionic or ionic resins and immobilized proteins, cells or tissue.
In many of the disease states multiple biochemical abnormalities exist, and due to the nature of the abnormal substances involved, multiple sorbent systems may be required. Such developments will take many years. Therefore due to the nature of the substances (larger molecular weights of generally over 100,000 daltons) or the nature of the disease state, where the specific macromolecule that is causative for the symptoms of the disease is not defined, the more general approach of removing all molecules over a specific molecular weight can be chosen. Membranes having a molecular cutoff of about 100,000 daltons are chosen as they can pass albumin thereby negating the need to infuse this plasma product as is done by the conventional plasmapheresis process.
Therefore it is an object of the invention to provide a plasmapheresis method and apparatus for removing macromolecules of predetermined size from a plasma solution.
A further object of the invention is to provide a plasmapheresis method and apparatus of the above type wherein a physiological solution is withdrawn from a patient, treated by removing macromolecules of predetermined size, and returned to the patient in a continuous process.
A further object is to remove molecules from the plasma which form a macromolecule after adding a complexing agent to the plasma.
A further object of the invention is to provide a plasmapheresis apparatus for "on-line" removal of macromolecules of predetermined size from a patient's physiological solution that is simple in construction, inexpensive to manufacture, and highly effective in operation.
Briefly the foregoing objects are accomplished by the provision of a method of removing macromolecules from a physiological solution including: securing a physiological solution stream such as blood from a patient; separating such physiological solution stream into a concentrated cellular element stream and a plasma stream containing macromolecules therein by either a centrifuge or a membrane filter; cooling such plasma stream to a temperature of between just above the freezing point of the plasma stream and 35.degree. centigrade; filtering macromolecules of predetermined size out of the cooled plasma stream to form a filtered plasma stream; combining such filtered plasma stream and such cellular element stream to form a processed stream; heating the processed stream to body temperature; and returning the heated processed stream to the patient in a continuous operation. In such method, the cooler cools the separated stream to a temperature between about just above the freezing point of the separated stream and about 35.degree. centigrade to cause such macromolecules to gel or precipitate. Also, a complexing agent may be added to the plasma to promote formation of macromolecules.
The invention also includes an apparatus for removing macromolecules from a patient's physiological solution such as blood including plasma separation means, such as a centrifuge or a membrane filter, for dividing a physiological solution containing macromolecules into a concentrated cellular element stream and a plasma stream, a cooler in fluid flow communication with the plasma separation means for receiving the plasma stream therefrom and cooling such plasma stream to cause the macromolecules therein to gel or precipitate, filter means such as a membrane filter in fluid flow communication with the cooling unit for receiving the cooled plasma stream therefrom and filtering such cooled plasma stream to remove macromolecules of a predetermined size therefrom, fluid flow communication means for receiving the filtered plasma stream from the filter means and for receiving the concentrated cellular element stream and combining the two last-named streams to form a processed stream for return to the patient. A pump may be employed in fluid flow communication with the plasma separation means and with the patient to pump the physiological solution from the patient to the plasma separation means. Instead of blood the physiological solution may be lympth or ascitic fluid. The cooling unit cools the separated plasma stream to a temperature of between just above the freezing point of the separated plasma stream and approximately 35.degree. centigrade. A heater unit may be operatively secured to the fluid flow communication means at a point in such fluid flow communication means after which the filtered plasma stream and the concentrated cellular element stream are combined to heat the processed stream to approximately body temperature before it is returned to the patient. As an alternative, the filter means may be encased in the cooling unit for receiving the cooled plasma stream therefrom to further cool such cooled plasma stream.
Other objects and advantages of the invention will be apparent from the following description taken in conjunction with the drawings wherein: